Disorders of the intestine, disorders of the colon, and disorders associated with or suspected of being associated with a dysfunctional intestine and/or dysfunctional colon, are an unmet medical need. The present invention comprises products, methods and uses which are useful in relation to treating such disorders.
More particularly, inflammatory Bowel Disease (IBD), which includes ulcerative colitis and Crohn's Disease, is a common disease with severe morbidity and an extremely limited therapeutic repertoire. In most cases, surgical intervention is necessary due to the failure of successful pharmacologic intervention. Improved therapy for IBD is therefore extremely desirable.
Current pharmacologic therapy for IBD is limited to steroids, sulfasalizine and TNF antibodies all of which have significant limitations due to side effects caused by the high levels of systemic administration that must be given to achieve therapeutic effects. The underlying causes of inflammatory bowel disease are not clearly understood but the symptoms have been treated through the use of anti-inflammatory agents that often are not specific and lead to serious side effects, especially if administered chronically. In addition to being toxic, most current anti-inflammatory therapeutics have limited solubility, permeability or stability resulting in high drug doses, frequent administration or administered by injection or suppositories, thus therapeutic options in IBD are very limited. Hydroxylase inhibitors have a potential role in the treatment of IBD. See The Hydroxylase Inhibitor Dimethyloxalylglycine Is Protective in a Murine Model of Colitis Gastroenterology, Volume 134, Issue 1, January 2008, Pages 156-165.e1. Eoin P. Cummins, Fergal Seeballuck, Stephen J. Keely, Niamh E. Mangan, John J. Callanan, Padraic G. Fallon, Cormac T. Taylor.
A permeable (“leaky”) intestinal epithelial barrier has been implicated in intestinal and extraintestinal diseases. Examples of such diseases are the intestinal diseases inflammatory bowel disease, celiac disease, Crohn's disease, ulcerative colitis, GI-GVHD, gastroenteritis, duodenitis, jejunitis, ileitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, pseudomembraneous colitis, irritable bowel syndrome including Irritable bowel syndrome-diarrhea predominant (IBS-D), irritable bowel syndrome-constipation predominant (IBS-C) and irritable bowel syndrome-mixed (IBS-M); diverticulosis, diverticulitis and endometriosis.
Extraintestinal disorders in which a leaky intestinal epithelial barrier have been implicated include rheumatic disorders, rheumatoid arthritis, temporomandibular joint syndrome, type 1 diabetes, multiple sclerosis, atopic dermatitis, psoriasis, a chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, depressive disorders, affective disorders and attention disorders, colorectal carcinoma, adenocarcinoma, and chronic heart failure.
For example, the reader is referred to Vaarala O, Atkinson M A, Neu J (October 2008). “The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity”. Diabetes 57 (10): 2555-62; Liu Z, Li N, Neu J (April 2005). “Tight junctions, leaky intestines, and pediatric diseases”. Acta Paediatr. 94 (4): 386-93; Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009 January; 22(1):75-83; de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, lardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni R, Bravaccio C. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 October; 51(4):418-24; Sandek A, Rauchhaus M, Anker S D, von Haehling S (September 2008). “The emerging role of the gut in chronic heart failure”. Curr Opin Clin Nutr Metab Care 11 (5): 632-9; Terjung B, Spengler U (February 2009). “Atypical p-ANCA in PSC and AIH: a hint toward a “leaky gut”?”. Clin Rev Allergy Immunol 36 (1): 40-51; Intestinal mucosal permeability in inflammatory rheumatic diseases. II. Role of disease. Mielants H, De Vox M, Goemaere S, Schelstraete K, Cuvelier C, Goethals K, Maertens M, Ackerman C, Veys E M, J. Rheumatol. 1991 March; 18(3):394-400; Intestinal mucosal permeability in inflammatory rheumatic diseases. I. Role of antiinflammatory drugs. Mielants H, Goemaere S, De Vos M, Schelstraete K, Goethals K, Maertens M, Ackerman C, Veys E M. J. Rheumatol. 1991 March; 18(3):389-93; Intestinal permeability and atopic disease. MacKie R M. Lancet. 1981 Jul. 18; 2(8238):155.
The reader is referred to a recent review by Andy Wullaert, Marion C Bonnet and Manolis Pasparakis in Cell Research (2011) 21:146-158 for an understanding of the role of NF-κB in the regulation of epithelial homeostasis and inflammation, and this publication and all the references mentioned in it are included herein by reference in their entirety. In summary, a number of in vivo studies in genetic mouse models over the past years have revealed that NF-κB inhibition can also trigger chronic inflammatory conditions. This function of NF-κB appears to be particularly important at epithelial surfaces, where NF-κB activity in epithelial cells is required for the maintenance of immune homeostasis. Therefore, proper regulation of NF-κB activation at epithelial interfaces is crucial for the maintenance of physiological tissue homeostasis and for efficient host defense against environmental insults. NF-κB inhibition sensitizes epithelial cells to stress-inducing stimuli coming either from the environment (e.g., microorganisms) or from immune cells (e.g., cytokines) and compromises their viability resulting in the deregulation of tissue immune homeostasis and triggering inflammation. Moreover, NF-κB is known to protect cells from a wide variety of cell death triggers.
A number of studies have showed that inhibition of NF-κB activation specifically in the intestinal epithelium causes severe intestinal inflammation. Thus, mice lacking NF-κB signaling protein NEMO specifically in intestinal epithelial cells (IECs) developed severe chronic colitis characterized by epithelial ulceration, elevated expression of proinflammatory mediators and infiltration of immune cells. Complete abrogation of canonical NF-κB activity in the intestinal epithelium, achieved by ablation of NEMO (or by combined deficiency of both IKK1 and IKK2), caused severe colon inflammation, demonstrating that IKK/NF-κB signaling performs essential homeostasis-preserving functions in the colonic epithelium. Patients carrying hypomorphic mutations in NEMO usually suffer from severe immunodeficiency and developmental skin defects, but some of these patients also develop colitis. Interestingly, hematopoietic stem cell transplantation (HSCT) is effective in treating the immunodeficiency, but does not improve the colitis phenotype. On the contrary, HSCT often worsens pre-existing colitis or even triggers colon inflammation in patients who did not suffer from it before transplantation, suggesting that impaired NF-κB signaling in non-hematopoietic cells is responsible for colitis development. It would therefore be desirable to up-regulate NF-κB activity in subjects who would benefit therefrom, for example in patients who suffer from or have suffered from inflammatory orders of the GI tract, for example those suffering from graft-versus host disease following HSCT.